(1) Field of the Invention
The chemical processes of the present invention produce novel antibacterial agents of the .beta.-lactam type containing a hitherto unknown nucleus and useful intermediates for their synthesis.
(2) Description of the Prior Art
Penicillins and cephalosporins comprise a group of well-known antibacterial agents commonly grouped together as a class called .beta.-lactam antibiotics. For a recent review of this field with many citations (especially the first ten) to the prior work, see J. P. Hou and J. W. Poole, .beta.-lactam Antibiotics: Their Physiocochemical Properties and Biological Activities in Relation to Structure, J. Pharmaceutical Sciences, 60(4), 503-532 (April, 1971). Most of the work in this field has fundamentally been done, speaking broadly, with 6-aminopenicillanic acid, 7-aminocephalosporanic acid and derivatives thereof produced by fermentation or chemical transformation of the natural products. Despite the extensive progress made in preparing active derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid, there is a continuing search for synthetic and semi-synthetic routes to new families of .beta.-lactam antibiotics which may possess more advantageous properties then those derived from the known pencillin and cephalosporin nuclei.
Considerable work has been done on total chemical synthesis of both known .beta.-lactams and nuclear analogs of such known compounds. A recent review is the text by M. S. Manhas and A. K. Bose, Synthesis of Penicillin, Cephalosporin C and Analogues, Marcel Decker, Inc., 95 Madison Avenue, New York, New York, 1969. Another extensive review is by R. B. Morin and B. G. Jackson, Chemistry of Cephalosporin Antibiotics, Fortschr. Chem. Org. Naturst., 28, 343-403 (1970), especially pages 379-393; the now famous "Woodward Intermediate" is shown therein as compound 146 on page 387. A more recent review of .beta.-lactams is that by M. S. Manhas and A. K. Bose, Beta-Lactams: Natural and Synthetic: Part 1, Wiley-Interscience, New York, New York, 1971. A still further review article on the synthesis of .beta.-lactams is that by A. K. Mukerjee et al., Synthesis, 327 (1973).
Other pertinent publications relating to synthesis of .beta.-lactams are:
(a) D. M. Brunwin, G. Lowe and J. Parker, J.C.S. Chem. Comm., 1971, 865-867, describing synthesis of nuclear analogs of the penicillin-cephalosporin group. PA1 (b) D. M. Brunwin et al., J. Chem. Soc. (C), 1971, 3756-3762 and J.C.S. Chem. Comm., 1972, 589-590 describing total synthesis of nuclear analogs of penicillins and cephalosporins. PA1 (c) S. Kukolja, J. Amer. Chem. Soc., 93, 6267-6270 (1971) and 94, 7590-7593 (1972) describing preparation of 6-phthalimido-5-epipenicillanates and disulfide analogs of penicillins. PA1 (d) J. S. Webber et al., J. Medicinal Chemistry, 14(11), 1136-1138 (1971) describing preparation of 3-cyanomethyl cephem nucleus. PA1 (e) West German Patent Specification 2,219,601 (Farmdoc 76,051T) describing synthesis of .beta.-lactams of the formula ##STR2## wherein X is halo, N.sub.3 -- or H.sub.2 N--, A is --S--, --S--CH.sub.2 --, --O--, --O--CH.sub.2 --, --CH.sub.2, --CH.sub.2 CH.sub.2 -- or --NH-- and R.sup.1, R.sup.2 and R.sup.3 are hydrogen, C.sub.1 -C.sub.6 alkyl or aryl. PA1 (f) U.K. Pat. No. 1,308,822 disclosing .beta.-lactams of the formula ##STR3## where Y=amino or substituted amino. (g) S. Wolft et al., Can. J. Chem., 50, 2894-2905 (1972) describing synthesis of sulfur-free penicillin derivatives. PA1 (h) French Pat. No. 2,111,859 describing nuclei of the formula ##STR4## and 7-acylated derivatives thereof. (i) Helvetica Chimica Acta, 55(2), 388-429 (1972) describing nuclear modified cephalosporins and penicillins. PA1 (j) F. Moll et al., Zeit. fur Naturforsch. B, 27(b)6, 727 (1972) describing nuclear analogs of cephalosporins. PA1 (k) U.K. Specifications 1,271,013 and 1,271,014 describing .gamma.-lactams of 7-(acylamino)-3-aminomethyl-ceph-3-em-4-carboxylic acids. PA1 (l) U.K. Pat. Specification No. 1,271,180 describing preparation of novel thiazoline azetidinone rearrangement products useful as intermediates in penicillin and cephalosporin synthesis. PA1 (m) German Pat. Specification Nos. 2,046,822, 2,046,823 and 2,046,824 describing synthesis of novel azetidinone intermediates. PA1 (n) G. Lowe et al., J. Chem. Soc. Perkins I, 1322 (1973) describing total synthesis of nuclear analogs of 7-methylcephalosporins having the formula ##STR5## (o) D. M. Brunwin et al., J. Chem. Soc. Chem. Comm., 865 (1971) describing synthesis of compounds of the formula ##STR6## (p) S. Wolfe et al., Canadian J. Chem., 50, 2902 (1972) describing compounds of the formula ##STR7## (q) J. P. Luttringer et al., Tetrahedron Letters, 4163-4166 (1973) describing compounds of the formula ##STR8## (r) U.S. Pat. No. 3,835,130 disclosing .beta.-lactams of the formula ##STR9## wherein R.sub.a and R.sub.b are each hydrogen or R.sub.a and R.sub.b form a covalent carbon-to-carbon bond, R.sub.1 ' represents hydrogen, R.sub.1 " is cyanoacetyl, bromacetyl or an acyl group of the formula ##STR10## in which Ar is phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyll, 3,5-dichloro-4-hydroxyphenyl or 2-thienyl, R.sub.2 ' is hydrogen and R.sub.3 ' is hydrogen or lower alkyl. PA1 (s) West German Offenlegungsschrift 2,355,209 describing synthesis of .beta.-lactams of the formula ##STR11## wherein R is acyl, A' is hydrogen, hydroxy, carbamoyloxy, thiocarbamoyloxy, quaternary ammonium, N-lower alkyl carbamoyloxy, N,N-di-lower alkyl carbamoyloxy, N-lower alkylthio and N,N-diloweralkylthiocarbamoyloxy, azido, halo, cyano, a tertiary amine, acyloxy, or a 5-member heterocyclic thio group having 1-4 hetero atoms; B is H, OCH.sub.3 or SR where R is lower alkyl or aryl; X is a divalent radical selected from --O--, --CH.sub.2 -- or --NY-- where Y is hydrogen, lower alkyl, formyl or benzyl and R' is hydrogen or a protecting group. PA1 (1) .alpha.-Amino-.alpha.-phenylacetamido include U.S. Pat. Nos. 3,641,021, 3,734,907, 3,687,948, 3,741,965, 3,757,015, 3,743,644, Japan 71/24400 (Farmdoc 46374S), Belgium 776,222 (Farmdoc 38983T; U.K. 1,328,340 which includes various substituents on the benzene ring), Bengium 772,592 (Farmdoc 19696T; U.S. Pat. Nos. 3,687,948, 3,734,907 and 3,757,012), West Germany 2,202,274 (Farmdoc 50428T) corresponding to U.S. Pat. No. 3,759,904, Netherlands 7205644 (Farmdoc 76309T; U.S. Pat. No. 3,757,014); U.S. Pat. Nos. 3,855,213 and 3,867,380; and PA1 (2) o-, m- or p-aminoethoxyphenylacetamido as Netherlands 72/13968 (Farmdoc 24740U) corresponding to U.S. Pat. No. 3,759,905 and PA1 (3) o-aminomethylphenylacetamido as Netherlands 72/06326 (Farmdoc 76374T) (which also reviews the older patent literature concerning substituted 7-phenylacetamidocephalosporanic acids) corresponding to U.S. Pat. No. 3,766,176 and 3,766,175; and PA1 (4) N-(phenylacetimidoyl)aminoacetamido as U.S. Pat. No. 3,692,779; and PA1 (5) .alpha.-amino-.alpha.-(1,4-cyclohexadienyl)acetamido as in Bengium 776,222 (Farmdoc 38983T; U.K. 1,328,340). PA1 (xii) Aminoacyl, for example EQU R.sup.g CH(NH.sub.2)-(CH.sub.2).sub.n CO- PA1 (xiii) Substituted glyoxylyl groups of the formula EQU R.sup.h.CO.CO-- PA1 (b) halogenating the 3-hydroxymethyl intermediate with a phosphorus halide, e.g., phosphorus trichloride, or phosphorus tribromide, to produce the desired 3-halomethyl derivative of formula VII. PA1 (a) 5% NaOH was used. PA1 (b) The second washing with ethanol was omitted. PA1 (c) Dry diethylether was used for washing and most of the water must be drained.
Replacement of the 3-acetoxy group of a cephalosporin by various heterocyclic thiols has been extensively discussed in the literature. Issued patents on 3-thiolated cephalosporins in which the 7-substituent is
Additional similar disclosures are found in U.S. Pat. No. 3,692,779 (Belgium 771,189; Farmdoc 12819T), Japan 72/05550 (Farmdoc 12921T), Japan 72/05551 (Farmdoc 12922T), U.S. Pat. No. 3,719,673 (Belgium 759,570; Farmdoc 39819S), Belgium 793,311 (Farmdoc 39702U) and Belgium 793,191 (Farmdoc 39684U).
Issued disclosures of 3-thiolated cephalosporins in which the 7-substituent is 7-mandelamido (7-.alpha.-hydroxyphenylacetamido) are found, for example, in U.S. Pat. No. 3,641,021, France 73.10112, U.S. Pat. No. 3,796,801, Great Britain 1,328,340 (Farmdoc 38983T), U.S. Pat. No. 3,701,775, Japan 4844293 (Farmdoc 55334U), U.S. Pat. No. 3,855,213, and in Hoover et al., J. Med. Chem. 17(1), 34-41 (1974) and Wick et al., Antimicrobial Ag. Chemo., 1(3), 221-234 (1972).
U.S. Pat. No. 3,819,623 (and, for example, also U.K. Pat. No. 1,295,841 and West Germany 1,953,861) discloses specifically and with working details the preparation of 2-mercapto-1,3,4-thiadiazole-5-acetic acid and its conversion to 7-(1H-tetrazol-1-yl-acetamido)-3-(5-carboxymethyl-1,3,4-thiadiazol-2-ylthi omethyl)-3-cephem-4-carboxylic acid which is also disclosed in West German Offenlegungsschrift 2,262,262.